The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometimes has deleterious side effects. A growing demand in pharmaceutical industries is to market a chiral drug in enantiomerically pure form.
To meet this challenge, chemists have explored many approaches for acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Among these methods, asymmetric catalysis is often the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. During the last two decades, great effort has been devoted to discovering new asymmetric catalysts and more than a half-dozen commercial industrial processes have used asymmetric catalysis as the key step in the production of enantiomerically pure compounds.
The majority of current asymmetric catalytic processes relies on transition metal catalysts bearing chiral ligands. Asymmetric phosphine ligands have played a significant role in the development of transition metal catalyzed asymmetric reactions. While certain metal catalyzed phosphine chiral ligands have shown acceptable enantioselectivities in numerous reactions, there are a variety of reaction in which only modest enantioselectivity has been achieved with these ligands. The use of enzymes as asymmetric catalysts is limited because very few pure enzymes have been found to facilitate highly enantioselective catalytic reactions.
Given the limitations with transition metal catalysts and enzymes, the use of organic catalysts for asymmetric synthesis has attracted increasing attention. Compared with transition metal catalysts, there are several advantages of using pure organic catalysts: recovery of organic catalysts generally is easy since the catalysts are covalently bound and relatively stable; no contamination of toxic heavy metals exists during the reaction; and pure organic catalysts, as compared to metal catalysts, are environmentally benign.
Several organic asymmetric catalysts have been discovered and used in industrial applications. For example, chiral phosphines are known to catalyze a number of organic reactions. Vedejs et al., in the Journal of Organic Chemistry ("J. Org. Chem."), Vol. 61, 8368 (1996), demonstrated phosphine-catalyzed enantioselective acylations of secondary alcohols. Whitesell and Felman, J. Org. Chem., Vol. 42, 1663 (1977), used nitrogen-based chiral auxiliaries such as trans 2,5-dimethylpyrrolidine for organic synthesis.
This invention discloses several new chiral heterocyclic compounds for asymmetric synthesis and catalysis. These compounds contain rigid ring structures useful for restricting conformational flexibility of the compounds, thus enhancing chiral recognition. The invention provides chiral heterocyclic compounds which contain phosphorous, nitrogen, and sulfur atoms within the ring structure. The chiral heterocyclic compounds disclosed in the invention allow for new catalytic asymmetric processes, including reactions proceeding by a variety of methods described herein. In such a manner, the invention provides an efficient and economical method with which to synthesize chiral drugs and agrochemicals.